Trisomy for the Down syndrome ‘critical region’ is necessary but not sufficient for brain phenotypes of trisomic mice

Abstract

Trisomic Ts65Dn mice show direct parallels with many phenotypes of Down syndrome (DS), including effects on the structure of cerebellum and hippocampus. A small segment of Hsa21 known as the 'DS critical region' (DSCR) has been held to contain a gene or genes sufficient to cause impairment in learning and memory tasks involving the hippocampus. To test this hypothesis, we developed Ts1Rhr and Ms1Rhr mouse models that are, respectively, trisomic and monosomic for this region. Here, we show that trisomy for the DSCR alone is not sufficient to produce the structural and functional features of hippocampal impairment that are seen in the Ts65Dn mouse and DS. However, when the critical region is returned to normal dosage in trisomic Ms1Rhr/Ts65Dn mice, performance in the Morris water maze is identical to euploid, demonstrating that this region is necessary for the phenotype. Thus, although the prediction of the critical region hypothesis was disproved, novel gene dosage effects were identified, which help to define how trisomy for this segment of the chromosome contributes to phenotypes of DS.

Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21

“…For example, cases 16 and 18 have cardiac anomaly, and the line (Figure 3) represents the region of overlap between the trisomic regions for these two cases (Figure 2). However, in addition to these data, we have data from many more cases (8,9,10,11,12,20,23 and 25) that do not have cardiac anomaly, but are also trisomic for at least a part of this region. For many phenotypes, this analysis may reduce the size of the candidate regions, but it has the problem that it does not take into account the complicating factor of reduced penetrance (Supplementary Figure S2).…”

“…Further, recent work on a mouse model either trisomic or monosomic for the syntenic DSCR found no evidence that the region was required to produce the characteristic facial phenotype, 11 and that it was necessary, but not sufficient, for the hippocampal phenotype seen in DS. 20 The limited number of partial trisomy samples, and low resolution of the mapping in earlier studies, restricted the identification of critical regions. Array comparative genome hybridization (aCGH) now allows high-resolution mapping of deletions and duplications using either oligonucleotides 21 or BAC clones.…”

Increased dosage of DYRK1A and DSCR1 delays neuronal differentiation in neocortical progenitor cells

“…In the developing neocortices, proliferation and differentiation of neural progenitors are impaired, suggesting misregulation of neocortical progenitors in DS (Chakrabarti et al 2007;Ishihara et al 2010). On the other hand, studies using mouse models that are trisomic for the DSCR alone show that the DSCR is necessary but not sufficient for certain brain phenotypes seen in Ts65Dn mice (Olson et al 2004(Olson et al , 2007. These studies suggest that phenotypes associated with DS are due to the complex effects of multiple genes in the human chromosome 21.…”

Trisomie 21 : 50 ans entre médecine et science

“…Des modèles murins porteurs ou non d'une duplication correspondant à la DSCR classique ont été construits. Ils montrent que les gènes de la région sont nécessaires, mais pas suffisants, pour produire les signes majeurs de la trisomie 21 [37,38]. L'hypothèse de gènes individuels sensibles à l'effet-dose, qui est à la base de la notion de DSCR, n'est pas vérifiée par ce modèle murin, qui plaide plutôt pour un modèle d'interactions multiples.…”